A. Chemistry
A variety of pregnane compounds having a cyano substituent at the 18-position have been described in the literature. Such compounds can be named as 18-cyanopregnanes or as pregnane-18-carbonitriles. Publications describing compounds of this type include the following:
(1) Kalvoda et al., Helv. Chim. Acta, 49, 424 (1966). PA0 (2) Kalvoda, Helv. Chim. Acta, 51, 267 (1968). PA0 (3) Kalvoda et al., Helv. Chim. Acta, 52, 2106 (1969). PA0 (4) Kalvoda et al., Helv. Chim. Acta, 55, 356 (1972). PA0 (5) Freerksen et al., J. Am. Chem. Soc., 99, 1536 (1977). PA0 (6) Auel et al., Steroids, 31, 367 (1978). PA0 (7) Holbert et al., Tetrahedron Letters, 26, 1137 (1985). PA0 (8) Viger et al., Tetrahedron, 44, 1127 (1988). PA0 (9) DE OLS No. 2 018 252 (publ. Oct. 29, 1970). PA0 (10) U.S. Pat. No. 3,092,627 (issued June 4, 1963). PA0 (11) U.S. Pat. No. 3,684,674 (issued Aug. 15, 1972).
As far as specific cyano compounds are concerned, 18cyanoprogesterone (3,20-dioxopregn-4-ene-l8-carbonitrile) has been described by Kalvoda et al. (1966), Kalvoda (1968), Auel et al., and U.S. Pat. No. 3,092,627. 18-Cyano-11.beta.-hydroxyprogesterone (11.beta.-hydroxy-3,20-dioxopregn-4-ene-l18carbonitrile) appears to have been described only by Kalvoda et al. (1972) although the corresponding compound in which the 3-ketone is protected as the ethylene ketal (with shifting of the 4-double bond to the 5-position) is described by Holbert et al. 18-Cyanohydrocortisone is described by U.S. Pat. No. 3,684,674 while 18-cyanoprednisolone is described by that same patent and also by Kalvoda et al. (1972). In addition to the specific compounds considered above, many other related compounds are also described in the above publications. Among such other compounds are progesterone derivatives in which one or both of the carbonyl groups are protected as ethylene ketals (with appropriate shifting of any double bond that may be present in the 4-position) or in which a carbonyl group is replaced by a hydroxy group (again with appropriate shifting of any double bond that may be present in the 4-position) The hydroxy group can optionally be further esterified or etherified to give compounds such as a 3-acetate, a 3-t-buty-l ether or a 3-(t-butyl)dimethylsilyl ether. Additionally described in the indicated articles are compounds which do not contain a double bond in the A- or B-ring, compounds which contain an 11-oxo substituent, and also compounds containing both an 11.beta.-hydroxy and a 9.alpha.-fluoro substituent.
All of the above publications describe the cyano compounds as intermediates in the preparation of other compounds. In only one case was there any indication that the cyano compounds had been tested for pharmacological activity. Thus, Auel et al. indicated that 18-cyanoprogesterone was tested in the Clauberg and anti-Clauberg tests (in rabbits) and found to be inactive. Otherwise, it is noted that DE No. 2 018 252 and U.S. Pat. No. 3,684,674, which are equivalent patents and which only describe compounds having a 17-hydroxy substituent, contain an assertion of pharmacological activity only with regard to final products obtained from intermediates containing a cyano substituent at the 18-position. However, it is noted that the C. A. abstract of the German patent and the Derwent abstract of the corresponding Belgian patent appear to contain incorrect indications that the cyano compounds possess pharmacological activity. That is, properties which the patents themselves attribute only to the final products described therein have been incorrectly attributed to cyano intermediates for those final products.